Abstract: In this SBIR application miRecule proposes to develop a microRNA-based therapeutic mimic of miR-30-5p (miRecule candidate MC-30) for the treatment of multi-drug resistant (MDR) cancers. Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common form of cancer. Greater than half of patients present with late stage III or IV disease, with an average 5-year survival rate of ~40%. HNSCC tumors have high levels of genetic mutations leading to high tumor heterogeneity and drug resistance. miR-30-5p expression is widely repressed in tumor tissues, and MIR30 gene deletion is observed in ~30% of HNSCCs. miR-based therapeutics offer a disruptive MDR cancer treatment by targeting both the primary oncogenic pathways and potentially suppressing mechanisms of intrinsic or acquired resistance. EGFR targeted therapy is often resisted by overexpression of the compensating growth factor receptors (GFRs) MET and IGF1R. We have made the novel discovery that miR-30-5p can target and repress all three of these GFRs. The rationale for our design is that a miR-30-5p mimic will be superior in its ability to treat heterogeneous late-stage HNSCC due to its ability to regulate not only EGFR, but also MET, IGF-1R, and over two dozen other mRNAs confirmed to be deregulated in tumor tissue and associated with over-proliferation, adhesion, migration, extracellular matrix remodeling, and differentiation. Our early study shows that a chemically modified mimic of miR-30-5p, exhibiting significantly improved efficacy over the biological microRNA, was effective at inhibiting tumor growth in vivo in a preclinical model of HNSCC. A significant hurdle for nucleic acid therapeutics is a lack of an efficient means of delivering them specifically to target cancer cells, especially at the metastatic stage. To overcome this obstacle, we employ two unique strategies. First, our chemically modified mimic of miR-30-5p has vastly improved nuclease stability and activity, decreasing the amount of mimic that needs to be present in the cell to produce the desired effect, and extending the duration of response. Second, our mimics are encapsulated in a clinically validated tumor- targeted liposomal nanodelivery system (scL). The nanocomplex carries an scFv antibody fragment against the transferrin receptor (TfR), which is up-regulated on the surface of most cancer cells and triggers uptake via receptor-mediated endocytosis. In this Phase I SBIR study we aim to we will characterize the half-life of our lead nuclease-stabilized mimic in HNSCC cells, targeting of multiple oncogenic mRNAs and signaling pathways, and test our hypothesis that it can more effectively combat drug resistance in vitro (Aim 1). We will test this mimic in a cetuximab and cisplatin-resistant orthotopic xenograft mouse model of HNSCC and compare directly with standard of care cisplatin and cetuximab. We will also assess potential toxicity and off- target effects. (AIM2) Successful completion of these studies will demonstrate the feasibility of MC-30 as a drug candidate and dosing regimen to be used in future PK, TOX, ADME, and other animal studies as required for an IND package. Once FDA approved and commercially available MC-30 will offer an effective treatment of MDR HNSCC and perhaps other cancers for which there are currently no treatment options.